PROJECT SUMMARY Increasing anal cancer incidence rates in the US are strongly influenced by the HIV epidemic with a 30-fold increased lifetime risk of anal cancer and a 4-fold increase in 5-year mortality among HIV-infected. Anal cancer incidence among HIV-infected men that have sex with men (MSM) in the US is comparable to cervical cancer incidence among women in sub-Saharan Africa. Anal cancer typically has a delayed diagnosis with 45-50% of patients presenting with disseminated disease and there are currently no national recommended screening guidelines for anal cancer. Pre-malignant anal lesions can progress to anal cancer and these lesions can be detected and treated. However, when pre-malignant lesions are treated, recurrence of high grade squamous intraepithelial neoplasia (HSIL) is high (65%) and often requires multiple treatments to the lesions. The lesion microenvironment, specifically the immune cells present, may play a role in lesion progression/regression and could be used as a biomarker to predict patient recurrence and disease-free survival. The role of tumor infiltrating lymphocytes (TILs) has been evaluated in several cancers and these cells are associated with increased survival outcomes. The proposed research project aims to evaluate the potential biological importance of TILs in patients with pre-malignant anal lesions and anal cancer. We will examine whether these TILs predict recurrence of the disease and disease-free survival. We will also determine whether peripheral lymphocytes are associated with clinical outcomes (recurrence) in HIV-infected MSM with pre-malignant anal lesion, which could then be used as a potential biomarker for disease outcomes. Through the career development award, the candidate will develop skills in tumor immunology and cancer biology research. These skills will be applied to conduct clinical cohort studies to identify biological mechanisms through which infections can cause cancer, and will aid the candidate to become an independent investigator in infection-related cancer research. The candidate has a strong background in epidemiologic research of the natural history of HPV-related disease. Vanderbilt University is the ideal institution to continue the candidate's training in infection-related cancer immunology, because it is home to leading scientists in the areas crucial for the candidate's training. Additionally, Vanderbilt houses major centers that rarely come together in one institution. The candidate will be mentored by leading experts in the fields of cancer epidemiology (Dr. Xiao Ou Shu), anal cancer (Dr. Timothy Geiger), gastrointestinal cancer pathology (Dr. Mary Kay Washington), tumor immunology (Dr. Young Kim), and HIV immunology (Dr. Spyros Kalams). With the knowledge and experience provided by this career development award, the candidate will be prepared to apply for R01 funding necessary to establish a multidisciplinary research program in infection-related cancers.